Cole, TJ

Fewtrell, M

Lucas, A

English

UCL Discovery

As a medical student (long beforeevidence based medicine) I was led tobelieve that in this situation there was verylittle risk of addiction. But my faith in thiscomforting idea was shaken by my experi­ence of being involved with the manage­ment of a mountaineer who had severefrostbite of the hands and feet in Nepal 40years ago. When in hospital in Kathmanduthe severe pain in his feet could only be con­trolled by opioids (pethidine). In discussionsabout the continued use of this drug I took arelaxed attitude because of the teaching Ihad received. The man later had to haveboth legs amputated below the knee. Duringthis time he became thoroughly addicted topethidine. The management of drug addi­tion was less developed in those days and hedecided to come off “cold turkey.” Hisexperience in achieving this is graphicallydescribed in his book, No Place for Man.2From what we know of the effect ofopioids in downregulating the opioid recep­tors it is hardly surprising that continued useof high doses of opioids even in opioid sen­sitive pain relief is likely to lead to addiction.The outcome, however, may well depend onthe dose and route of administration.I agreewith McQuay that we urgently need morehard data.James S Milledge physician emeritusNorthwick Park Hospital, Harrow HA1 3UJ1 McQuay H. Opioids in chronic non­malignant pain. BMJ2001;322:1134­5. (12 May.)2 Mulgrew P. No place for man. London: Nicholas Vane, 1964.Chronic pain should not be undertreatedEditor—I am a patients' advocate andliterature researcher, not a physician. Ininternet community service work I have cor­responded with hundreds of patients withchronic face pain. Many of these havediagnosed facial neuralgias or neuropathies.Many report that one or more doctors haverefused to treat them with opioids, even on atrial basis. Some report having been accusedof drug seeking behaviour simply forcommitting the offence of requesting treat­ment with drugs that they know fromexperience are effective for them. In thehealth insurance system in the United Statesthe consequences of such a comment in apatient's medical record can be horrendous.I recognise that treatment with opioids isgenerally less effective for the categories ofpain that I see than for the general popu­lation. But from long exposure to online dis­cussions between patients themselves, I knowthat some people do get relief from individualopioids or “cocktails” tailored by a painspecialist. I am forced by this experience tocondemn outright the refusal of many medi­cal professionals to even try such measures,inthe absence of other effective medical or sur­gical remedies. I heartily endorse research toassess factors related to patients and efficacyof drugs, as suggested by McQuay.1It is long past time to put to rest themyth that prescribed pain drugs createaddiction problems on the street. This issueshould be readily susceptible to simpleretrospective studies. How many convicteddrug offenders in the United States orUnited Kingdom have been prescribedopioids by a doctor? Surely these numbersare known or can readily be derived?Drug offenders tend to come from popu­lation cohorts that are among the least servedby medical caregivers. In the United States,the evidence is strong that medical practicefor pain management is about to undergo apopular revolution. What a shame that theprocess had to be forced by patients' lawsuits,rather than proceeding from simple commonsense and compassion on the part of profes­sional caregivers. If you are one of those doc­tors who continue to withhold pain manage­ment measures from your patients, then Isuggest that you need refresher training incurrent practice for pain management.Richard A Lawhern network contactTrigeminal Neuralgia Association (US), Sterling,VA 20165, USAlawhern@erols.com1 McQuay H. Opioids in chronic non­malignant pain. BMJ2001;322:1134­5. (12 May.)Don't forget methadone for chronic painEditor—McQuay in his editorial says thatthe use of opioids for chronic non­malignantpain can be messy, but this need not be so.1The risks and benefits of opioids are wellattested. The study of fentanyl patches versuslong acting morphine is an imperfectcomparison of one expensive opioid deliverysystem with another.2 McQuay chose manu­facturers' recommendations over numerousclinical alternatives. Medical trials are oftenrepresented as a race with a clear winner. Inthis case, the winner happens to be the prod­uct of the company sponsoring the trial.McQuay's question on treating pain respon­sive to opioids presupposes that a patient hasalready tried opioids. We could instead askwhether doctors should deny opioids to apatient who seems to benefit from them?Withdrawing such drugs may be unwise oreven unethical.Differences between various opioids areto be expected because their effects areindividual and doses never exactly compar­able.Since this trial was not blind,the claim ofmodest advantages for fentanyl is notscientifically robust, as McQuay points out.Some reported improvements may also stemfrom the novelty factor, with a patch deliverysystem. Transdermal patches have certainbenefits, but they also have problems. Doseadjustments are not easy,disposal can be haz­ardous,and adhesion can be a problem,espe­cially in countries where people usually bathedaily. The choice of drug for chronic painshould not ignore the safety profiles oftraditional opioids such as oral methadone,morphine, or codeine. From its use inaddiction, methadone has exemplary longterm safety data. It is also taken once daily.Although it is a cheap drug and perhaps ofless interest to drug companies, methadonecan be highly effective for chronic pain.Clinicians should always consider thesafest and most effective drug initially,moving to other options if problems arise.Cost is also a factor, especially in conditionsrequiring long term pharmacotherapy. Anystigma from methadone or morphinequickly vanishes when these drugs are usedappropriately. Fentanyl patches shouldprobably not be used as first line treatment.Likewise, long acting morphine, which isexpensive and generally administered twicedaily, should probably be second linetreatment to methadone. If methadone isfound to be unsatisfactory, buprenorphine,oxycodone,morphine (long or short acting),and fentanyl are all viable alternatives.Despite the best science, the use of suchopioids is still often based on trial and error.Andrew Byrne general practitionerDrug and Alcohol, Redfern, New South Wales,2016, AustraliaAB makes a proportion of his income from treatingaddiction and pain management patients. Notobacco sponsorship. No cruel animal experimentsperformed in this practice.1 McQuay H. Opioids in chronic non­malignant pain. BMJ2001;322:1134­5. (12 May.)2 Allan L, Hays H, Jensen N­H, Le Polain de Waroux B, BoltM, Donald R, et al. Randomised crossover trial of transder­mal fentanyl and sustained release oral morphine fortreating chronic non­cancer pain. BMJ 2001;322:1154­8.Early growth and coronaryheart disease in later lifeAnalysis was flawedEditor—Eriksson et al concluded that inFinnish men born 60 years ago “low weightgain during infancy is associated withincreased risk of coronary heart disease,” yetthey did not analyse infant weight gain.1 Alltheir references to infant growth relate tosize at 1 year (table 3). Had they applied thekey regression models that we havedescribed2 to separate the effects of weight atdifferent ages on later outcome, they wouldhave found that infant weight gain was unre­lated to risk of coronary heart disease.In their simultaneous analysis the hazardratios for birth weight and weight at 1 yearwere similar and less than 1, showing thatgreater weight during infancy is protective.Weight gain is weight at 1 year less weight atbirth, so if weight gain were protective itwould appear as a protective effect of weightat 1 year and a relatively deleterious effect ofweight at birth.2 But the two effects wereequally protective, so weight gain in infancy(strictly,upwards centile crossing) is unrelatedto later coronary heart disease.The hazard ratios for weight at birth andat 1 year can be rearranged as hazard ratiosfor mean weight and weight gain. The hazardratio for weight gain is equal approximatelyto the square root of the ratio of the hazardratios at 1 year and at birth—that is,Ö­­­­ 0.84/0.94=0.95. This is similar to the birth­weight hazard ratio, which was not significant(95% confidence interval 0.83 to 1.06).During childhood, increasing fatnesswas related to increased risk of coronaryheart disease, particularly in those who wereinitially thin.1 This corresponds to our inter­action model.2 The hazard ratio for thechange in body mass index from age 1 toage 12 is obtainable from our combinedLetters572 BMJ VOLUME 323 8 SEPTEMBER 2001 bmj.commodel. The hazard ratios for body massindex at ages 1 and 12 are 0.83 and 1.03(table 4).On the assumption that they wouldbe similar if fitted simultaneously, the squareroot of the ratio of hazard ratios gives theapproximate hazard ratio for the change inbody mass index, Ö­­­­ 1.03/0.83=1.11—notthat different from 1.20.So we agree that infant thinness andsubsequent increasing fatness are synergisticrisk factors for coronary heart disease, asothers have shown.3 But for centile crossingto relate to coronary heart disease thehazard ratios for body size at the start andend of the period should differ significantly,and this is not the case in infancy. Routineuse of our approach2 would have avoidedthis confusion.T J Cole professor of medical statisticsCentre for Paediatric Epidemiology andBiostatistics, Institute of Child Health, LondonWC1N 1EHtim.cole@ich.ucl.ac.ukM Fewtrell MRC senior clinical scientistA Lucas MRC clinical research professorMRC Childhood Nutrition Research Centre,Institute of Child Health1 Eriksson JG, Forsén T, Tuomilehto J, Osmond C, BarkerDJP. Early growth and coronary heart disease in later life:longitudinal study. BMJ 2001;322:949­53. (21 April.)2 Lucas A, Fewtrell M, Cole TJ. Fetal origins of adultdisease—the hypothesis revisited. BMJ 1999;319:245­9.3 Frankel S, Elwood P, Sweetnam P, Yarnell J, Smith GD.Birthweight, body mass index in middle age and incidentcoronary heart disease. Lancet 1996;348:1478­80.Authors' replyEditor—Cole et al are wrong. Coronaryheart disease is clearly related to low weightgain during infancy in addition to low birthweight. Conditional on birth weight, theadditional predictive power of infant weightgain is expressed by a ÷2 statistic of 9.26(P=0.002). In a simultaneous analysis thehazard ratio for a one standard deviationdecrease in birth weight is 1.29 (95%confidence interval 1.14 to 1.45, P<0.001)and for a one unit decrease in standarddeviation scores for weight between birthand age 1 it is 1.21 (1.08 to 1.36, P=0.001).The mistake that Cole et al make is inparameterising the model so that part of theeffect of infant weight gain is lost in an aver­age weight term.It is not adequate to analyse data onbirth weight and weight at age 1 using whatthey describe as key regression models.These are dependent on assumptions of lin­earity.In the analyses of data from Hertford­shire, which first established the linkbetween coronary heart disease and lowweight gain in infancy, it was necessary todevelop a more complicated model andexpress the results by using contours of dis­ease risk.1 The Helsinki study provides astriking replication of these results and alsoallows us to examine the effects of growththrough childhood. In our paper we focusedon the finding that the effects of childhoodweight gain on later coronary heart diseaseare conditioned by ponderal index at birth(birth weight/length3).Because the Helsinki dataset includes anaverage of nine measurements of height andweight during infancy for 8760 men andwomen we can now pinpoint the time ininfancy when growth faltering begins andrelate this to infant feeding, housingconditions, family size, and other variables.The study allows, for the first time, detaileddescription of the paths of fetal, infant, andchildhood growth that precede the develop­ment of chronic diseases in later life. Whenthese descriptions are published, would­becommentators on our analyses will bewelcome to have any additional data neededfor clarification. This will avoid the kind oferroneous conclusions that have beendrawn by Cole et al.C Osmond medical statisticianD J P Barker professor of clinical epidemiologyMRC Environmental Epidemiology Unit(University of Southampton), SouthamptonGeneral Hospital, Southampton SO16 6YDco@mrc.soton.ac.ukJ G Eriksson senior researcherT Forsén research fellowNational Public Health Institute, Department ofEpidemiology and Health Promotion, Diabetes andGenetic Epidemiology Unit, FIN­00300 Helsinki,Finland1 Barker DJP, Osmond C, Winter PD, Margetts B, SimmondsSJ. Weight in infancy and death from ischaemic heart dis­ease. Lancet 1989;ii:577­80.Riluzole for motor neuronediseaseReply from chairman of appraisalcommittee at NICEEditor—In commenting on the NationalInstitute for Clinical Excellence's guidanceon riluzole Sandercock et al show the differ­ence between assessment and appraisal ofevidence.1 One form of evidence used in anappraisal is a formal systematic review. Theassessment report does not make recom­mendations on how the technology shouldbe used in the NHS; that is the job of theinstitute's appraisal committee. The com­mittee also receives submissions frompatient and professional organisations,which provide perspectives not captured bya formal review of published evidence.The committee takes account of theclinical need of patients and the broadbalance of benefits and costs of the technol­ogy. Its conclusions are subject to consulta­tion and can be appealed against. This is allsome distance on from the original assess­ment of the evidence.Sandercock et al suggest that a superfi­cial reading of the guidance may not give anadequate understanding of the evidencebase for riluzole. The institute's guidanceidentifies what the committee considered tobe important elements of the evidence. Thefull assessment report is available on theinstitute's website (www.nice.org.uk). Neitherdocument, however, can fully convey thedepth of the committee's consideration ofthe evidence.Sandercock et al advise clinicians to pre­scribe in accordance with riluzole's licence,say that patients offered the drug should befully informed, and suggest further research.This is fully in accordance with the institute'sguidance.In the same cluster of letters Wheatleyand Gray accuse the institute of recom­mending a treatment “when there is no sig­nificant evidence of benefit.”1 Although thestatistical measures of benefit may not begreat (we acknowledge that the relative haz­ard reduction for tracheostomy free survivalis 12% (that is, 1.00­0.88), not 17% as quotedin the guidance), the committee is requiredto consider what the reported measures ofclinical effectiveness of the technology actu­ally mean to people with the disease.Wheatley and Gray say that the guid­ance is contrary to the conclusions of theSandercock report. We do not look to theauthors of assessment reports for conclu­sions as, unlike the appraisal committee,they have neither access to the full evidencebase nor the range of skills necessary toundertake an appraisal.The institute's guidance need not deterfurther research into this disease or its treat­ment. The guidance sets out a clear researchagenda, which we would encourage themanufacturer and clinicians to pursue.David Barnett chairman of appraisal committeeNational Institute for Clinical Excellence, LondonWC2N 5HRnice@nice.nhs.uk1 Correspondence.Riluzole for motor neurone disease.BMJ2001;322:1305­6. (26 May.)Any placebo controlled trial of riluzolewould surely be unethical nowEditor—We are concerned about the opin­ions expressed by Sandercock et al regard­ing the clinical efficacy of riluzole for theamyotrophic lateral sclerosis form of motorneurone disease and the appropriateness ofthe guidance issued by the National Institutefor Clinical Excellence (NICE).1Riluzole has been subject to regulatoryscrutiny by the European Agency for theEvaluation of Medicinal Products and theFood and Drug Administration; an inde­pendent review by the Cochrane Collabora­tion2; and the review by the NationalInstitute for Clinical Excellence. The healthtechnology assessment report by Sander­cock et al formed only part of the evidencebased assessment by the institute; evidencefrom a wide range of expert clinical,research, and patient based sources was alsomade available.Of particular importance are the resultsof two large prospective, randomised, dou­ble blind placebo controlled trials of riluzolein amyotrophic lateral sclerosis.34The studyby Bensimon et al (n=155) was stopped at18 months because of a clear difference infavour of the active treatment arm.3 As aresult, patients taking placebo were offeredactive treatment, which meant that theauthors were unable to determine overallsurvival in comparison with survival withplacebo. However, analysis of the study to 18months showed that patients taking riluzolehad a 28% better survival rate than thosetaking placebo (P=0.014).Letters573 BMJ VOLUME 323 8 SEPTEMBER 2001 bmj.com

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